The rising global prevalence of Alzheimer disease (AD) has heightened the urgency to develop effective AD therapeutics. Many lines of evidence support the hypothesis that AD pathogenesis involves dysfunctional innate immune effector cells in both the periphery and central nervous system (CNS). Innate immunity promotes tissue repair, clearance of debris, release of cytokines and chemokines which act to signal appropriate interface with adaptive immune responses. However, dysregulation of CNS innate immune cells, microglia, or of peripheral monocytes, contributes to a neurotoxic environment directly injuring synapses, creating a feed forward loop of neural injury. Recent technological advances have produced powerful tools to survey the molecular regulators of the innate immune network contributing to AD pathogenesis. MicroRNAs, a class of small non-coding RNAs, have emerged as powerful modulators of CNS and peripheral innate immunity, regulating pro-inflammatory activity, phagocytosis and contributing to mechanisms of A? clearance. MiRNA profiles are altered in brain tissue, serum and CSF of patients with AD. In particular, miR146 and miR155, proximal inflammatory modulating miRNAs, are dysregulated in AD implicating miRNAs in the inflammatory arm of AD pathogenesis. Work by our group and others have demonstrated that miR146 and miR155 participate in in the development of age-dependent chronic inflammation in vivo. These data underscore putative pathways by which AD pathogenesis is influenced by inflammatory miRNA regulatory networks. In this multi-PI proposal, we have designed a systems approach to investigate the role of miRNAs in CNS and circulating innate immune cell regulation in the context of AD. MicroRNA profiling, gene co- expression analysis and amyloid-? (A?) clearance studies will be performed in peripheral macrophage and microglia-like cells differentiated from individuals with early symptomatic AD and early or asymptomatic carriers of familial autosomal dominant Alzheimer disease genes (PSEN1, PSEN2 and APP). In parallel, we will employ the murine APP/PS1 and 5XFAD AD models to determine the impact of altered miR146 and miR155 expression in vivo on cognitive deficits, synapse loss, A? clearance and chronic CNS inflammation. By capturing the inflammatory miRNA landscape and inflammatory profile in patients destined to develop dementia of the Alzheimer type and modeling microRNA modulation in vivo, we aim to identify targetable pathways which leverage the bidirectional communication between CNS and peripheral inflammation.